Several amphetamines, many of which are popular illicit drugs of abuse, produce long-term neurotoxicity to dopaminergic and/or serotonergic neurons in experimental animals. Interestingly, the type of monoaminergic neuron damaged depends on both the analog injected as well as the species of animal used. It is not known why some amphetamines are selectively toxic to serotonergic neurons whereas others affect both systems or only dopaminergic neurons nor why the neurotoxic profile for the amphetamines differs between the mouse and rat. Furthermore, the mechanisms by which these compounds produce neurotoxicity are unknown. The amphetamines release both dopamine (DA) and serotonin (5HT) and it has been hypothesized that oxygen-derived products resulting from the oxidation of these monoamines may be the toxic species. Additionally, methamphetamine-induced damage to dopaminergic neurons can be prevented by antagonists of the N-methyl-D-aspartate (NMDA) receptor, one of the subtypes of the glutamate receptor. These findings indicate that an excitotoxic mechanism may be involved in the neurotoxic process. The hypothesis to be tested is that the facilitated release of the monoamines by the amphetamines leads to free radical generation and a release of excitatory amino acids which results in a tremendous increase in oxidative stress in dopaminergic nerve terminals. The goal of our research is to gain a better understanding of amphetamine-induced neuropathology. The aims of the proposed studies are 1) to characterize and investigate reasons for the differential neurotoxicity of various amphetamines on monoaminergic neurons in both mice and rats, 2) to further evaluate the involvement of the excitatory amino acids and oxidative stress in amphetamines-induced toxicity to monoaminergic neurons and 3) to determine the extent to which DA and 5HT release produced by the various amphetamines contributes to dopaminergic or serotonergic toxicity.. The studies will be conducted in mice and rats. Characterizing the species differences should help to delineate the mechanisms underlying neurotoxicity. Biochemical techniques and pharmacological agents will be used to study the effects of the amphetamines. An understanding of the mechanisms by which the amphetamines damage monoaminergic neurons has important implications not only for amphetamine abuse but for disorders of unknown etiology such as Parkinson's Disease, schizophrenia and depression in which there are abnormalities in dopaminergic and serotonergic function.